The mutational landscape of medullary thyroid carcinoma using whole-exome sequencing in China.

6054 Background: Medullary thyroid carcinoma (MTC) is a rare malignancy, and its molecular pathogenesis is far from being understood. Therefore, a relatively comprehensive and accurate genomic profiling is needed for the future molecular diagnosis, treatment and early prevention of MTC patients. Methods: In this study, we investigated both the somatic and germline mutational spectrum of MTC, whole-exome sequencing (WES) was performed on tumor samples and matched noncancerous tissues from 30 MTC patients. Genetic alterations were defined and analyzed using MutSigCV and novel germline mutations were identified using MutationTaster and cross-referenced in PubMed. Results: In somatic mutational spectrum we found the top three significantly mutated genes (SMGs) in our MTC samples were RET, FAM186A and PRG4 genes (33%, 33% and 27%, respectively). For the germline mutations, FAT4 was detected as the most common mutated genes, following by RET and FAT1. Besides, we identified 30 novel germline mutations such as IGF1R, PDK1, NOTCH1, RPTOR, MPL, SETD2 and ARID2. Those mutated genes have been previously associated with neurofibromatosis, Lynch syndrome and other diseases respectively and now predicted potential functional pathogenicity in the patients with MTC. Conclusions: The study elucidated a relatively more comprehensive genomic landscape of MTC. In addition to the RET gene, which has been studied extensively, other SMGs may also be of interest including novel germline mutations. These findings may indicate the potential basis of molecular diagnosis, early prevention and targeted therapeutic options for patients with MTC in the future.